Program Director/Principal Investigator (Last, First, Middle): PD: Pascual, V. OVERVIEW PROJECT SUMMARY We propose an integrated, cooperative Center for Lupus Research (CLR) based at the Baylor Institute for Immunology Research in Dallas, TX, and the Jackson Laboratory for Genomic Medicine in Farmington, CT. The goal of the CLR is to advance the knowledge of pathways and mechanisms that contribute to the development and amplification of human Systemic Lupus Erythematosus (SLE), and to develop assays and tools to i) monitor these dysfunctional pathways and ii) stratify patients towards personalized therapies. The scope and goals of the CLR are based on data accumulated through longitudinal assessment of pediatric lupus patients followed for over a decade. Using validated clinical measures of disease activity (DA) and blood gene expression profiling, we identified gene signatures correlating with DA at the cohort level. Personalized immunomonitoring revealed, however, significant heterogeneity in molecular pathways correlating with DA at the individual patient level. We now propose to capitalize on the expression profiling approaches we pioneered, while leveraging the outstanding power of new genomic technologies, to address how the three most prevalent signatures, related to IFN, Myeloid cells and Plasmablasts/Plasma Cells, underpin SLE pathogenesis. Towards our goal, we gathered a multidisciplinary team of scientists (including immunologists, molecular biologists, bioinformaticians and software engineers) and Physician-Scientists/Clinicians with deep experience in the clinical management of SLE. This team has worked efficiently together for years?from bedside-to-bench and from bench-to-bedside?to understand and treat human immunological diseases. The CLR is structured around two complementary research projects, each of which adopts a translational, technology-driven approach to understanding key molecular aspects of SLE. In Project 1, we will dissect cellular and molecular components of these signatures. The analysis will proceed to the single cell level, will include flares and remissions, and will interrogate steady and activation states. In Project 2, we will characterize the repertoire of immune cell isoforms and epigenome profiles associated with the three major SLE molecular groups. In both projects we will incorporate cutting-edge technologies and build upon our established expertise in molecular immune profiling. The projects will be critically supported by two research cores. The Center's Clinical and Sample Core will oversee all aspects of clinical assessment, clinical data collection and sample storage and distribution. The Center's Genomics and Data Management Core will provide state-of-the-art genomics technologies and data management capabilities for the Center. The Administrative Core will ensure effective communication across the Center, and oversee pilot projects that complement the scope and goals of the core. Successful completion of these projects will yield an unprecendented knowledgebase of genomic and functional data, as well as novel molecular targets for new diagnostics or personalized therapeutics that could transform the clinical management of SLE. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page